Over the last few decades, concern has heightened over the potential hormone-like effects of environmental chemicals on the reproductive health of fish, wildlife, and humans. The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant, produced by various chemical reactions and combustion processes, including waste incineration, and has been shown in animals to be a potent endocrine disruptor. On July 10,1976, as a result of a chemical explosion, residents of Seveso, Italy experienced the highest levels of TCDD exposure in a human population. We followed up the women 20 years after the accident to determine whether they were at higher risk for reproductive disease. Women aged 0 to 40 years at the time of the explosion, and who lived in Zones A or B were interviewed extensively about their reproductive and pregnancy histories; had a blood draw, pelvic exam, and transvaginal ultrasound; and were asked to complete a menstrual diary. Serum specimens stored from the time of the explosion were analyzed to determine individual levels of TCDD exposure. The Seveso Women's Health Study, originally funded in 1996 (R01 ES07171) aimed to examine the relationship of serum TCDD levels and endometriosis. Continued funding in 1999 allowed the analysis of additional serum specimens for TCDD and examination of the relation to other reproductive endpoints: menstrual cycle characteristics, age of menarche, fetal loss and birthweight, age at menopause, and breast cancer incidence. The present application focuses on the health and function of the ovaries, uterus, and breast in order to document the substantial evidence in animals. Specifically, we aim to determine the relation of serum TCDD levels to fertility (time to conception and clinical infertility); ovarian function (number of ovarian follicles, presence of functional ovarian cysts, serum hormone levels); uterine health (uterine volume, endometrial thickness, and the occurrence/number of fibroids); the occurrence of benign breast disease, and the initiation/duration of lactation. We also will examine whether the above relationships are modified by developmental status (i.e., pre- or post-menarche) at the time of TCDD exposure. The Seveso Women's Health Study is the only comprehensive study to date of the reproductive health of a human female population exposed to TCDD. This study has the benefit of being a large cohort study with a wide range of TCDD exposure, documented by individual-level TCDD measured in sera collected soon after the explosion.